1. Field of the Invention
The present invention relates generally to the treatment of bladder cancer with viral therapy agents and, in particular, to agents and methods for enhancing recombinant oncolytic virus transduction of the bladder epithelium.
2. Background of the Technology
Bladder cancer is a commonly occurring cancer and more than 50,000 new cases are diagnosed every year. Bladder cancer is a superficial disease confined to the mucosa in the majority of patients. Of the various therapeutic modalities available, transurethral resectioning of the tumor is considered to be the most effective treatment for the management of superficial bladder cancer. However, 70% of these superficial bladder tumors will recur after endoscopic resectioning, and 20% progress to life-threatening invasive diseases within 2 years of cystectomy. See Raghavan, et al., “Biology and Management of Bladder Cancer”, N. Engl. J. Med., 322, 16, 1129-1138 (1990).
Gene therapy has also been used for the treatment of bladder cancer. See, for example, Brewster, et al., Eur. Urol. 25, 177-182 (1984); Takahashi, et al., Proc. Natl. Acad. Sci. USA 88, 5257-5261 (1991); and Rosenberg, J. Clin. Oncol., 10, 180-199 (1992).
In vitro studies using cell lines derived from human bladder tissues have demonstrated efficient transgene expression following infection with recombinant adenovirus. Bass, et al., Cancer Gene Therapy 2, 2, 97-104 (1995). Experiments in vivo have also shown adenovirus transgene expression in the urinary bladder of rodents after intravesical administration. Bass, et al., supra; Morris, et al., J. Urology, 152, 506-550 (1994). In vitro experiments with wild-type adenovirus demonstrate that virus attachment and internalization is not influenced by benzyl alcohol, but do demonstrate an enhanced uncoating of the virion. Blixt. et al., Arch. Virol., 129, 265-277 (1993).
In vivo studies have demonstrated that various agents (e.g. acetone, DMSO, protamine sulfate) can break down the protective “mucin” layer that protects the bladder epithelium from bacteria, viruses and other pathogens. See, for example, Monson, et al., J. Urol., 145, 842-845 (1992) and Parsons, et al., J. Urol., 143, 139-142 (1990). Methods of modifying the bladder surface to enhance gene transfer have also been disclosed. Siemens. et al., “Evaluation of Gene Transfer Efficiency by Viral Vectors to Murine Bladder Epithelium”, J. of Urology, 165, 667-671 (2001).
U.S. Pat. No. 6,165,779 discloses a gene delivery system formulated in a buffer comprising a delivery-enhancing agent such as ethanol or a detergent. The gene delivery system may be a recombinant viral vector such as an adenoviral vector.
There still exists a need, however, for improved gene therapy methods and agents which can accomplish direct, optimal, in vivo gene delivery to the bladder epithelium.